One of the most severe daily problems in Prader-Willi syndrome (PWS) is the inability to reach satiety after a meal, which leads to hyperphagia and obesity. The loss of expression of two small nucleolar RNA (snoRNA) clusters is a crucial genetic contributor to the disease. One of these snoRNAs (SNORD115) promotes the most active form of the serotonin receptor 2C (HTR2C). Activated HTR2C receptors in the arcuate nucleus inhibit food uptake. We developed an oligonucleotide (oligo#5) that similar to SNORD115 promotes the formation of the most active HTR2C receptor that localizes on the cell surface. Oligo#5 inhibits food uptake of fasted mice when delivered by intracerebroventricular (ICV) or carotid injection to the arcuate nucleus. We postulate that oligo#5 could be developed into an anti hyperphagia drug for Prader-Willi syndrome. This hypothesis will be tested in two Specific Aims: 1. Deliver oligo#5 and its derivatives to the arcuate nucleus in the brain and determine their mode of action. We will test delivery using osmotic pumps bringing oligo#5 into the 3rd ventricle, similar to the acute injections. Oligo#5 accumulates in the hypothalamus and decreases food uptake after carotid injection, suggesting it can cross the blood brain barrier. We will therefore test delivery by injecting into the bloodstream. Different chemistries of oligo#5 wil be tested in cell-based models prior to testing in mice. This allows to determine efficacy and to get mechanistic insights. 2. Determine long term toxicity, efficacy and off-site targets of the oligonucleotide. We did not observe adverse effects in up to three repeated injections and will test long-term delivery using osmotic pumps and injection into the blood. We will determine immune response, behavioral changes, inflammation and other adverse effects and measure changes in efficacy over time. Off-target effects will be measured by RNA sequencing and array analysis. We expect that oligo#5 is safe, can be delivered through the bloodstream and shows a long-term reduction in food intake. These investigations are significant, as they target hyperphagia, the most complicating feature in the daily lives of patients, they are innovative as they deliver a nucleic acid to a brain region possibly through the blood, where it acts by changing target RNA processing; they are feasible, as we developed the oligonucleotide and the detection system.